Method for Treating Vasculitis

Abstract

A method of treating anti-neutrophil cytoplasmic antibodies-associated vasculitis (ANCA-associated vasculitis) in a patient eligible for treatment is provided involving administering an antagonist that binds to a B-cell surface marker, such as CD20 antibody, to the patient in a dose of about 400 mg to 1.3 grams at a frequency of one to three doses within a period of about one month. Another method of treating ANCA-associated vasculitis in a subject eligible for treatment is provided involving administering an effective amount of an antibody that binds to a B-cell surface marker to the subject to provide an initial exposure and a subsequent exposure to the antibody within certain dosing regimens. Further provided are articles of manufacture useful for such methods.

1 . A method of treating anti-neutrophil cytoplasmic antibodies-associated vasculitis (ANCA-associated vasculitis) in a patient comprising administering a CD20 antibody to the patient in a dose of about 400 mg to 1.3 grams at a frequency of one to three doses within a period of about one month.  
     
     
         2 . The method of  claim 1  wherein the dose is about 500 mg to 1.2 grams.  
     
     
         3 . The method of  claim 1  wherein the dose is about 750 mg to 1.1 grams.  
     
     
         4 . The method of  claim 1  wherein the antibody is administered in two to three doses.  
     
     
         5 . The method of  claim 1  wherein the antibody is administered in three doses.  
     
     
         6 . The method of  claim 1  wherein the antibody is administered within a period of about 2 to 3 weeks.  
     
     
         7 . The method of  claim 6  wherein the period is about three weeks.  
     
     
         8 . The method of  claim 1  wherein the ANCA-associated vasculitis is Wegener's granulomatosis.  
     
     
         9 . The method of  claim 1  wherein the ANCA-associated vasculitis is microscopic polyangiitis.  
     
     
         10 . The method of  claim 1  wherein a second medicament is administered in an effective amount, wherein the CD20 antibody is a first medicament.  
     
     
         11 . The method of  claim 10  wherein the second medicament is more than one medicament.  
     
     
         12 . The method of  claim 10  wherein the second medicament is a chemotherapeutic agent, an immunosuppressive agent, a disease-modifying anti-rheumatic drug (DMARD), a cytotoxic agent, an integrin antagonist, a non-steroidal anti-inflammatory drug (NSAID), a cytokine antagonist, or a hormone, or a combination thereof.  
     
     
         13 . The method of  claim 12  wherein the second medicament is a steroid or an immunosuppressive agent or both.  
     
     
         14 . The method of  claim 13  wherein the second medicament is a steroid.  
     
     
         15 . The method of  claim 14  wherein the steroid is a corticosteroid.  
     
     
         16 . The method of  claim 15  wherein the steroid is prednisone, prednisolone, methylprednisolone, hydrocortisone, or dexamethasone.  
     
     
         17 . The method of  claim 14  wherein the steroid is administered in lower amounts than are used if the CD20 antibody is not administered to a patient treated with steroid.  
     
     
         18 . The method of  claim 13  wherein the second medicament is an immunosuppressive agent.  
     
     
         19 . The method of  claim 18  wherein the immunosuppressive agent is cyclophosphamide, chlorambucil, mycophenolate mofetil, leflunomide, azathioprine, or methotrexate.  
     
     
         20 . The method of  claim 19  wherein the immunosuppressive agent is cyclophosphamide.  
     
     
         21 . The method of  claim 13  wherein the second medicament is a steroid and an immunosuppressive agent.  
     
     
         22 . The method of  claim 1  wherein the patient has never been previously treated with a CD20 antibody.  
     
     
         23 . The method of  claim 1  wherein the patient has not relapsed with the vasculitis.  
     
     
         24 . The method of  claim 1  wherein the antibody is a naked antibody.  
     
     
         25 . The method of  claim 1  wherein the antibody is conjugated with another molecule.  
     
     
         26 . The method of  claim 25  wherein the other molecule is a cytotoxic agent.  
     
     
         27 . The method of  claim 1  wherein the antibody is administered intravenously.  
     
     
         28 . The method of  claim 1  wherein the antibody is administered subcutaneously.  
     
     
         29 . The method of  claim 1  wherein no other medicament than the CD20 antibody is administered to the subject to treat the ANCA-associated vasculitis.  
     
     
         30 . The method of  claim 1  wherein the antibody is rituximab.  
     
     
         31 . The method of  claim 1  wherein the antibody is humanized 2H7 comprising the variable domain sequences in SEQ ID Nos. 2 and 8.  
     
     
         32 . The method of  claim 1  wherein the antibody is humanized 2H7 comprising the variable domain sequences in SEQ ID NOS:39 and 40.  
     
     
         33 . The method of  claim 1  wherein the antibody is humanized 2H7 comprising the variable domain sequences in SEQ ID NOS:32 and 33.  
     
     
         34 . The method of  claim 1  wherein the antibody is humanized 2H7 comprising a variable heavy-chain domain with alteration N100A, or D56A and N100A, or D56A, N100Y, and S100aR in SEQ ID NO:8 and a variable light-chain domain with alteration M32L, or S92A, or M32L and S92A in SEQ ID NO:2.  
     
     
         35 . The method of  claim 1  wherein the patient has a BVAS/WG score of 0 at six months after administration of the antibody.  
     
     
         36 . The method of  claim 1  wherein the patient has an elevated level of a anti-nuclear antibodies (ANA), anti-rheumatoid factor (RF) antibodies, creatinine, blood urea nitrogen, anti-endothelial antibodies, anti-neutrophil cytoplasmic antibodies (ANCA), or a combination thereof.  
     
     
         37 . An article of manufacture comprising: 
 a. a container comprising a CD20 antibody; and    b. a package insert with instructions for treating anti-neutrophil cytoplasmic antibodies-associated vasculitis (ANCA-associated vasculitis) in a patient, wherein the instructions indicate that a dose of the CD20 antibody of about 400 mg to 1.3 grams at a frequency of one to three doses is administered to the patient within a period of about one month.    
     
     
         38 . The article of  claim 37  further comprising a container comprising a second medicament, wherein the CD20 antibody is a first medicament, further comprising instructions on the package insert for treating the patient with the second medicament.  
     
     
         39 . The article of  claim 38  wherein the second medicament is a chemotherapeutic agent, an immunosuppressive agent, a cytotoxic agent, an integrin antagonist, a cytokine antagonist, or a hormone.  
     
     
         40 . The article of  claim 38  wherein the second medicament is a steroid or an immunosuppressive agent or both.  
     
     
         41 . A method of treating anti-neutrophil cytoplasmic antibodies-associated vasculitis (ANCA-associated vasculitis) in a subject comprising administering an effective amount of a CD20 antibody to the subject to provide an initial antibody exposure followed by a second antibody exposure, wherein the second exposure is not provided until from about 16 to 54 weeks from the initial exposure.  
     
     
         42 . The method of  claim 41  wherein the second exposure is not provided until from about 20 to 30 weeks from the initial exposure.  
     
     
         43 . The method of  claim 41  wherein the second exposure is not provided until from about 46 to 54 weeks from the initial exposure.  
     
     
         44 . The method of  claim 41  wherein each of the initial and second antibody exposures is provided in amounts of about 0.5 to 4 grams.  
     
     
         45 . The method of  claim 41  wherein each of the initial and second antibody exposures is provided in amounts of about 1.5 to 3.5 grams.  
     
     
         46 . The method of  claim 41  wherein each of the initial and second antibody exposures is provided in amounts of about 1.5 to 2.5 grams.  
     
     
         47 . The method of  claim 41  additionally comprising administering to the subject an effective amount of the CD20 antibody to provide a third antibody exposure, wherein the third exposure is not provided until from about 46 to 60 weeks from the initial exposure.  
     
     
         48 . The method of  claim 47  wherein the third antibody exposure is provided in an amount of about 0.5 to 4 grams.  
     
     
         49 . The method of  claim 47  wherein the third antibody exposure is provided in an amount of about 1.5 to 3.5 grams.  
     
     
         50 . The method of  claim 47  wherein the third antibody exposure is provided in an amount of about 1.5 to 2.5 grams.  
     
     
         51 . The method of  claim 47  wherein the third exposure is not provided until from about 46 to 55 weeks from the initial exposure.  
     
     
         52 . The method of  claim 47  wherein no further antibody exposure is provided until at least about 70-75 weeks from the initial exposure.  
     
     
         53 . The method of  claim 52  wherein no further antibody exposure is provided until about 74 to 80 weeks from the initial exposure.  
     
     
         54 . The method of  claim 41  wherein one or more of the antibody exposures is provided to the subject as a single dose of antibody.  
     
     
         55 . The method of  claim 54  wherein each antibody exposure is provided to the subject as a single dose of antibody.  
     
     
         56 . The method of  claim 41  wherein one or more of the antibody exposures is provided to the subject as separate doses of the antibody.  
     
     
         57 . The method of  claim 56  wherein each antibody exposure is provided as separate doses of the antibody.  
     
     
         58 . The method of  claim 56  wherein the separate doses are from about 2 to 3 doses.  
     
     
         59 . The method of  claim 56  wherein the separate doses constitute a first and second dose.  
     
     
         60 . The method of  claim 56  wherein the separate doses constitute a first, second, and third dose.  
     
     
         61 . The method of  claim 56  wherein a later dose is administered from about 1 to 20 days from the time the previous dose was administered.  
     
     
         62 . The method of  claim 56  wherein a later dose is administered from about 6 to 16 days from the time the previous dose was administered.  
     
     
         63 . The method of  claim 56  wherein a later dose is administered from about 14 to 16 days from the time the previous dose was administered.  
     
     
         64 . The method of  claim 56  wherein the separate doses are administered within a total period of between about 1 day and 4 weeks.  
     
     
         65 . The method of  claim 56  wherein the separate doses are administered within a total period of between about 1 and 25 days.  
     
     
         66 . The method of  claim 56  wherein the separate doses are administered about weekly, with the second dose being administered about one week from the first dose and any later dose being administered about one week from the previous dose.  
     
     
         67 . The method of  claim 56  wherein each separate dose of antibody is about 0.5 to 1.5 grams.  
     
     
         68 . The method of  claim 56  wherein each separate dose of antibody is about 0.75 to 1.3 grams.  
     
     
         69 . The method of  claim 41  wherein 4 to 20 antibody exposures are administered to the subject.  
     
     
         70 . The method of  claim 41  wherein a second medicament is administered in an effective amount with an antibody exposure, wherein the CD20 antibody is a first medicament.  
     
     
         71 . The method of  claim 70  wherein the second medicament is administered with the initial exposure.  
     
     
         72 . The method of  claim 70  wherein the second medicament is administered with the initial and second exposures.  
     
     
         73 . The method of  claim 70  wherein the second medicament is administered with all exposures.  
     
     
         74 . The method of  claim 70  wherein the second medicament is a chemotherapeutic agent, an immunosuppressive agent, a disease-modifying anti-rheumatic drug (DMARD), a cytotoxic agent, an integrin antagonist, a non-steroidal anti-inflammatory drug (NSAID), a cytokine antagonist, or a hormone, or a combination thereof.  
     
     
         75 . The method of  claim 70  wherein the second medicament comprises a steroid or an immunosuppressive agent or both.  
     
     
         76 . The method of  claim 75  wherein the second medicament is a steroid.  
     
     
         77 . The method of  claim 76  wherein the steroid is a corticosteroid.  
     
     
         78 . The method of  claim 77  wherein the steroid is prednisone, prednisolone, methylprednisolone, hydrocortisone, or dexamethasone.  
     
     
         79 . The method of  claim 76  wherein the steroid is administered in lower amounts than are used if the CD20 antibody is not administered to a subject treated with steroid.  
     
     
         80 . The method of  claim 75  wherein the second medicament is an immunosuppressive agent.  
     
     
         81 . The method of  claim 80  wherein the immunosuppressive agent is cyclophosphamide, chlorambucil, leflunomide, mycophenolate mofetil, azathioprine, or methotrexate.  
     
     
         82 . The method of  claim 81  wherein the immunosuppressive agent is cyclosphosphamide.  
     
     
         83 . The method of  claim 75  wherein the second medicament comprises a steroid and an immunosuppressive agent.  
     
     
         84 . The method of  claim 71  wherein the second medicament is not administered with the second exposure, or is administered in lower amounts than are used with the initial exposure.  
     
     
         85 . The method of  claim 41  wherein about 2-3 grams of the CD20 antibody is administered as the initial exposure.  
     
     
         86 . The method of  claim 85  wherein about 1 gram of the CD20 antibody is administered weekly for about three weeks as the initial exposure.  
     
     
         87 . The method of  claim 85  wherein the second exposure is at about six months from the initial exposure and is administered in an amount of about 2 grams.  
     
     
         88 . The method of  claim 85  wherein the second exposure is at about six months from the initial exposure and is administered as about 1 gram of the antibody followed in about two weeks by another about 1 gram of the antibody.  
     
     
         89 . The method of  claim 85  wherein about 1 gram of the CD20 antibody is administered followed in about two weeks by another about 1 gram of the antibody as the initial exposure.  
     
     
         90 . The method of  claim 89  wherein the second exposure is at about six months from the initial exposure and is administered in an amount of about 2 grams.  
     
     
         91 . The method of  claim 89  wherein the second exposure is at about six months from the initial exposure and is administered as about 1 gram of the antibody followed in about two weeks by another about 1 gram of the antibody.  
     
     
         92 . The method of  claim 85  wherein a steroid is administered to the subject before or with the initial exposure.  
     
     
         93 . The method of  claim 92  wherein the steroid is not administered with the second exposure or is administered with the second exposure but in lower amounts than are used with the initial exposure.  
     
     
         94 . The method of  claim 92  wherein the steroid is not administered with third or later exposures.  
     
     
         95 . The method of  claim 41  wherein the subject has never been previously treated with a CD20 antibody.  
     
     
         96 . The method of  claim 41  wherein the subject is in remission after the initial or a later antibody exposure.  
     
     
         97 . The method of  claim 41  wherein the subject is in remission when provided the second antibody exposure.  
     
     
         98 . The method of  claim 97  wherein the subject is in remission when provided all antibody exposures.  
     
     
         99 . The method of  claim 41  wherein the initial and second antibody exposures are with the same CD20 antibody.  
     
     
         100 . The method of  claim 41  wherein all antibody exposures are with the same CD20 antibody.  
     
     
         101 . The method of  claim 41  wherein the antibody is a naked antibody.  
     
     
         102 . The method of  claim 41  wherein the antibody is conjugated with another molecule.  
     
     
         103 . The method of  claim 102  wherein the other molecule is a cytotoxic agent.  
     
     
         104 . The method of  claim 41  wherein the antibody is administered intravenously.  
     
     
         105 . The method of  claim 104  wherein the antibody is administered intravenously for each antibody exposure.  
     
     
         106 . The method of  claim 41  wherein the antibody is administered subcutaneously.  
     
     
         107 . The method of  claim 106  wherein the antibody is administered subcutaneously for each antibody exposure.  
     
     
         108 . The method of  claim 41  wherein no other medicament than the CD20 antibody is administered to the subject to treat the ANCA-associated vasculitis.  
     
     
         109 . The method of  claim 41  wherein the ANCA-associated vasculitis is Wegener's granulomatosis.  
     
     
         110 . The method of  claim 41  wherein the ANCA-associated vasculitis is microscopic polyangiitis.  
     
     
         111 . The method of  claim 41  wherein the antibody is rituximab.  
     
     
         112 . The method of  claim 41  wherein the antibody is humanized 2H7 comprising the variable domain sequences in SEQ ID Nos. 2 and 8.  
     
     
         113 . The method of  claim 41  wherein the antibody is humanized 2H7 comprising the variable domain sequences in SEQ ID NOS:39 and 40.  
     
     
         114 . The method of  claim 41  wherein the antibody is humanized 2H7 comprising the variable domain sequences in SEQ ID NOS:32 and 33.  
     
     
         115 . The method of  claim 41  wherein the antibody is humanized 2H7 comprising a variable heavy-chain domain with alteration N100A, or D56A and N100A, or D56A, N100Y, and S100aR in SEQ ID NO:8 and a variable light-chain domain with alteration M32L, or S92A, or M32L and S92A in SEQ ID NO:2.  
     
     
         116 . The method of  claim 41  wherein the subject has a BVAS/WG score of 0 at six months after administration of the antibody.  
     
     
         117 . The method of  claim 41  wherein the subject has an elevated level of anti-nuclear antibodies (ANA), anti-rheumatoid factor (RF) antibodies, creatinine, blood urea nitrogen, anti-endothelial antibodies, anti-neutrophil cytoplasmic antibodies (ANCA), or a combination thereof.  
     
     
         118 . The method of  claim 41  wherein each of the antibody exposures is provided to the subject as a single dose or as two or three separate doses of antibody.  
     
     
         119 . An article of manufacture comprising: 
 a. a container comprising a CD20 antibody; and    b. a package insert with instructions for treating anti-neutrophil cytoplasmic antibodies-associated vasculitis (ANCA-associated vasculitis) in a subject, wherein the instructions indicate that an amount of the antibody is administered to the subject that is effective to provide an initial antibody exposure followed by a second antibody exposure, wherein the second exposure is not provided until from about 16 to 54 weeks from the initial exposure.    
     
     
         120 . The article of  claim 119  wherein each of the antibody exposures is provided to the subject as a single dose or as two or three separate doses of antibody.  
     
     
         121 . The article of  claim 119  wherein each of the initial and second antibody exposures is provided in an amount of 0.5 to 4 grams.  
     
     
         122 . The article of  claim 119  further comprising a container comprising a second medicament, wherein the CD20 antibody is a first medicament, and further comprising instructions on the package insert for treating the subject with the second medicament.  
     
     
         123 . The article of  claim 122  wherein the second medicament is a chemotherapeutic agent, an immunosuppressive agent, a cytotoxic agent, an integrin antagonist, a cytokine antagonist, or a hormone.  
     
     
         124 . The article of claim  125  wherein the second medicament is a steroid or an immunosuppressive agent or both.